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Patients with severe anaemia who refuse or cannot safely receive red cell transfusion present challenges during pregnancy, delivery and the postpartum period. Strategies including HBOC-201 (Hemopure) and intraoperative use of cell salvage have been used in non-pregnant patients to improve oxygen carrying capacity; however, these products pose unique risks in pregnant patients, those with sickle cell disease (SCD) and those undergoing caesarean section (C-section). We describe a case of a pregnant sickle beta+thalasasaemia patient who presented at 27 weeks gestation with pre-eclampsia and severe anaemia. As a Jehovah’s Witness, she declined allogenic blood transfusion. The patient successfully underwent emergent C-section with cell salvage and received HBOC-201 immediately after delivery, during the operative procedure. To our knowledge, this is the first published report documenting a Jehovah’s Witness patient with SCD who successfully received cell salvage and then HBOC-201 immediately postdelivery.

The sunken ship motif is frequently found in films and artistic installations on migrants, as it symbolizes their perilous crossing. As Michel Foucault asserts, the ship is “the heterotopia par excellence,” and the contemporary fate of migrant barges is quite comparable to that of the ship of fools described by the philosopher in the classical age. The ship is a heterotopic motif which acts as a physical substitute for the body of the castaway, a substitute that makes sense in the maritime world, and that we find in classical paintings, in popular religious art, or even in the ex-votos. The objects that belonged to migrants perished at sea have a memorial character, allowing their history and sometimes their identity somehow to be restored. Giving them back their name is an essential issue so that they can be buried and not wander in a heterotopic space after their death, a heterotopic wandering which also characterizes the experience of their migratory journey.

Background Serum free light chain (sFLC) assays are interpreted using a sFLC-ratio-based reference interval (manufacturer’s interval) that was defined using a cohort of healthy patients. However, renal impairment elevates the sFLC-ratio, leading to a high false positive rate when using the manufacturer’s interval. Prior studies have developed renal-specific reference intervals; however, this approach has not been widely adopted due to practical limitations. Thus, there remains a critical need for a renally robust sFLC interpretation method. Methods Retrospective data mining was used to define patient cohorts that reflect the spectrum of renal function seen in clinical practice. Two new reference intervals, one based on the sFLC-ratio and one based on a novel principal component analysis (PCA)-based metric, were developed for the FREELITE assay (Binding Site) on the Roche Cobas c501 instrument (Roche). Results Compared to the manufacturer’s reference interval, both new methods exhibited significantly lower false positive rates and greater robustness to renal function while maintaining equivalent sensitivity for monoclonal gammopathy (MG) diagnosis. While not significantly different, the point estimate for sensitivity was highest for the PCA-based approach. Conclusion Renally robust sFLC interpretation using a single reference interval is possible given a reference cohort that reflects the variation in renal function observed in practice. Further studies are needed to achieve sufficient power and determine if the novel PCA-based metric offers superior sensitivity for MG diagnosis. These new methods offer the practical advantages of not requiring an estimated glomerular filtration rate result or multiple reference intervals, thereby lowering practical barriers to implementation.

Introduction: Lymphedema remains a risk for 13–34% of breast cancer patients who require an axillary dissection (ALND) and radiation. Immediate lymphovenous anastomosis (LVA) may mitigate lymphedema by up to 30% by restoring the physiologic lymphatic drainage immediately after ALND. Currently, completion of ALND (cALND) versus radiation after neoadjuvant therapy (NAC) is being addressed by the Alliance A11202 trial, leaving a paucity of data to guide practice. Our study describes the implementation process of LVA into clinical practice after NAC for node-positive breast cancer in the current clinical context. Methods: We reviewed a prospective database of LVA in node-positive patients (cT1-4,Nany) who received NAC followed by axillary surgery ± immediate LVA from October 2021 to 2022. The evolution of the surgical approach is described. Specifically, patients who downstaged to clinically negative nodes post-NAC were offered targeted SLNB with dual-tracer and intraoperative frozen section (FS). Patients were reminded that the standard of care for any node positive is cALND. Immediate cALND with LVA was performed for grossly positive nodes or all positive SLNs; cALND was omitted for those with negative SLNs. For a microscopic disease on a frozen section, a shared decision was made pre-operatively, given each patient’s differing valuations of the benefit and risks of cALND ± LVA versus no cALND with planned regional radiation postoperatively. LVA was offered as an option as part of our institutional evaluation of the procedure. Results: A total of 15 patients were included; the mean age was 49.9 (range 32–75) with stage IIA to IIIB breast cancer. Of these, 6 (40%) were triple negative, 5 (33.3%) HER-2 positive, and 4 (26.7%) ER/PR+ HER-2 negative. There were 13 women (86.7%) who had persistent axillary adenopathy based on clinical and/or ultrasound assessment, with 8 patients proceeding directly to ALND with LVA. Among these patients, 3 (37.5%) had pathologic nodal disease, and 5 (62.5%) were node negative, confirming the limitations of pre-operative imaging. As a result, the subsequent 7 (46.7%) underwent targeted SLNB with FS, with 3 patients (42.9%) avoiding an ALND as a result of a negative FS. A total of 4 patients (57.1%) had 1 or more positive lymph nodes on FS: 3 proceeded with a cALND and LVA, and 1 patient (14.2%) opted for no cALND based on a pre-operative discussion and received adjuvant radiation and chemotherapy. Of the 11 patients who underwent ALND and LVA, 1 patient (9.1%) developed lymphedema at 6.9 months following their surgery. The accuracy, sensitivity, and specificity of pre-operative US were 46.7%, 85.7%, and 12.5% and intraoperative FS were 88.0%, 72.7%, and 100%, respectively. Conclusions: As adjuvant nodal radiation and systemic therapy continue to improve, the benefit of a cALND in patients with the limited residual disease remains unclear as we await the outcomes from clinical trials. In the era of clinical uncertainty, we propose a nuanced approach to the axilla by utilizing a shared decision model with patients, incorporating targeted SLNB with FS and completion node dissection when required and desired by the patient, coupled with LVA in a simple stepwise treatment pathway.

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This article presents a critical literature review on the security aspects of field-programmable gate array (FPGA) devices. FPGA devices present unique challenges to cybersecurity through their reconfigurable nature. The article also pays special attention to emerging system-on-chip (SoC) FPGA devices that incorporate a hard processing system (HPS) on the same die as the FPGA logic. While this incorporation reduces the need for vulnerable external signals, the HPS in SoC FPGA devices adds a level of complexity that is not present for stand-alone FPGA devices. This added complexity necessarily hands over the task of securing the device to developers. Even with standard security features in place, the HPS might still have unhindered access to the FPGA logic. A single software flaw could open up a breach that might allow an attacker to extract the FPGA’s configuration data. A robust cybersecurity strategy is thus required for developers. As such, this work aims to provide the groundwork to build a solid threat-based cybersecurity design strategy that is specially adapted to SoC FPGA devices.

Osteochondral allograft transplantation provides components of both cartilage and subchondral bone and can be used in large and multifocal defects where autologous procedures are limited by donor-site morbidity. Osteochondral allograft transplantation is particularly appealing in the management of failed cartilage repair, as larger defects and subchondral bone involvement are often present, and the use of multiple overlapping plugs might be considered. The described technique provides our preoperative workup and reproducible surgical approach for patients who have undergone previous osteochondral transplantation with graft failure and are young, active patients who would not be otherwise suited for a knee arthroplasty procedure.

Invasive breast carcinoma is a combination of heterogeneous diseases with distinct molecular and clinical features. Some subsets of breast cancer present major clinical challenges, including triple-negative, metastatic/recurrent disease and rare breast histologies. Previously, we developed a unique resource of 37 hard-to-treat breast cancer patient-derived xenografts (PDX). This set included mainly triple negative breast cancer (TNBC) patients that presented poor response to neoadjuvant chemotherapies (Savage et al. 2020 - PMID: 32546838). PDXs accurately reproduce the molecular heterogeneity of the primary tumors and show that multi-drug chemoresistance was retained upon xenotransplantation. Here, we present the characterization of PDX 3-dimensional cultures organoids (8) and PDX derived epithelial cell lines (11). Using single-cell RNAseq we showed that an organoid cultured for several passages (P8) maintained the heterogeneity of the matched PDX. Although in different proportions, all cancer cell populations found in the PDX were retained in matched organoids supporting that organoids are suitable models that recapitulates the tumor heterogeneity and are therefore a suitable model for drug screening. Among our new PDXs models (30), we have developed four PDXs from rare metaplastic breast cancers (MpBC), an aggressive subtype of breast cancer that present the poorest response to standard of care chemotherapy. We also developed one male breast cancer PDX with matched organoid. Omic analysis on our pre-clinical models and patient primary tumor and metastasis will inform development of therapeutic opportunities. This molecular information will guide selection of compounds that will be validated using our high throughput organoid drug screening pipeline. This will allow rapid screens of thousands of approved drugs, enhancing drug repurposing with potential for rapid clinical translation. The combined use of 3D tumor organoids and PDXs, is an important opportunity poised to transform identification of new therapeutic options for hard-to-treat lethal breast cancers. Citation Format: Hellen Kuasne, Anne-Marie fortier, Sandrine Busque, Simon Mathien, Paul Savage, Constanza Martinez Ramirez, Anie Monast, Margarita Soleinova, Atilla Omeroglu, Jamil Asselah, Nathaniel Bouganim, Sarkis Meterissian, Mark Basik, Morag Park. Development and molecular characterization of hard-to-treat breast cancer pre-clinical models to enhance precision medicine [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-09.

Background: Infiltration of cluster of differentiation (CD) 3+ (CD3+) T cells into the synovium and synovial fluid occurs in most patients with posttraumatic osteoarthritis. During disease progression, proinflammatory T helper 17 cells and anti-inflammatory regulatory T cells infiltrate the joint in response to inflammation. This study aimed to characterize the dynamics of regulatory T and T helper 17 cell populations in synovial fluid from equine clinical patients with posttraumatic osteoarthritis to determine whether phenotype and function are associated with potential immunotherapeutic targets. Hypothesis: An imbalance of the ratio of regulatory T cells and T helper 17 cells would be associated with disease progression in posttraumatic osteoarthritis, suggesting opportunities for immunomodulatory therapy. Study Design: Descriptive laboratory study. Methods: Synovial fluid was aspirated from the joints of equine clinical patients undergoing arthroscopic surgery for posttraumatic osteoarthritis resulting from intra-articular fragmentation. Joints were classified as having mild or moderate posttraumatic osteoarthritis. Synovial fluid was also obtained from nonoperated horses with normal cartilage. Peripheral blood was obtained from horses with normal cartilage and those with mild and moderate posttraumatic osteoarthritis. Synovial fluid and peripheral blood cells were analyzed by flow cytometry, and native synovial fluid was analyzed by enzyme-linked immunosorbent assay. Results: CD3+ T cells represented 81% of lymphocytes in synovial fluid, which increased in animals with moderate posttraumatic osteoarthritis to 88.3% ( P = .02). CD14+ macrophages were doubled in those with moderate posttraumatic osteoarthritis compared with mild posttraumatic osteoarthritis and controls ( P < .001). Less than 5% of CD3+ T cells found within the joint were forkhead box P3 protein+ (Foxp3+) regulatory T cells, but a 4- to 8-times higher percentage of nonoperated and mild posttraumatic osteoarthritis joint regulatory T cells secreted interleukin (IL)–10 than peripheral blood Tregs ( P < .005). T regulatory-1 cells that secreted IL-10 but did not express Foxp3 accounted for approximately 5% of CD3+ T cells in all joints. T helper 17 cells and Th17-like regulatory T cells were increased in those with moderate posttraumatic osteoarthritis ( P < .0001) compared with mild and nonoperated patients. IL-10, IL-17A, IL-6, chemokine (C-C motif) ligand (CCL) 2 (CCL2), and CCL5 concentrations detected by enzyme-linked immunosorbent assay in synovial fluid were not different between groups. Conclusions: An imbalance of the ratio of regulatory T cells and T helper 17 cells and an increase in T helper 17 cell–like regulatory T cells in synovial fluid from joints with more severe disease provide novel insights into immunological mechanisms that are associated with posttraumatic osteoarthritis progression and pathogenesis. Clinical Relevance: Early and targeted use of immunotherapeutics in the mitigation of posttraumatic osteoarthritis may improve patient clinical outcomes.

ObjectiveTo examine the incidence of perioperative blood transfusion and association with 30 day postoperative outcomes in gynecologic cancer surgery.MethodsThe American College of Surgeons National Surgical Quality Improvement Program database was queried to identify all gynecologic oncology cases from 2013 to 2019. Clinical and surgical characteristics and 30 day postoperative complications were retrieved. The primary outcome was 30 day composite morbidity, based on the occurrence of one or more of the 18 adverse events. Secondary outcomes were 30 day mortality, length of stay in hospital, and composite surgical site infection, defined as superficial, deep, or organ space surgical site infection. The χ2test and logistic regression analyses were performed to compare the outcomes of patients with and without perioperative blood transfusion.ResultsThere were 62 531 surgical gynecologic oncology cases with an overall transfusion incidence of 9.4%. The transfusion incidence was significantly higher at 22.4% with laparotomy compared with 1.7% with minimally invasive surgery (pConclusionPerioperative blood transfusion is associated with increased composite morbidity and prolonged length of stay in hospital. Preoperative patient optimization and institutional practices should be reviewed to improve the use of blood bank resources and adherence to restrictive blood transfusion protocols.

Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy. Significance: Single-cell transcriptomic profiling and multiomic cross-validation to uncover therapeutic targets identifies 38 myeloma marker genes, including 11 transcribing surface proteins with previously uncharacterized potential for targeted antitumor therapy.

We report the discovery of two warm sub-Neptunes transiting the bright (G = 9.5 mag) K-dwarf HD 15906 (TOI 461, TIC 4646810). This star was observed by the Transiting Exoplanet Survey Satellite (TESS) in sectors 4 and 31, revealing two small transiting planets. The inner planet, HD 15906 b, was detected with an unambiguous period but the outer planet, HD 15906 c, showed only two transits separated by ∼ 734 d, leading to 36 possible values of its period. We performed follow-up observations with the CHaracterising ExOPlanet Satellite (CHEOPS) to confirm the true period of HD 15906 c and improve the radius precision of the two planets. From TESS, CHEOPS, and additional ground-based photometry, we find that HD 15906 b has a radius of 2.24 ± 0.08 R and a period of 10.924709 ± 0.000032 d, whilst HD 15906 c has a radius of 2.93+−000607 R and a period of 21.583298+−00000055000052 d. Assuming zero bond albedo and full day-night heat redistribution, the inner and outer planet have equilibrium temperatures of 668 ± 13 K and 532 ± 10 K, respectively. The HD 15906 system has become one of only six multiplanet systems with two warm (700 K) sub-Neptune sized planets transiting a bright star (G ≤ 10 mag). It is an excellent target for detailed characterization studies to constrain the composition of sub-Neptune planets and test theories of planet formation and evolution., Monthly Notices of the Royal Astronomical Society, 523 (2), ISSN:13652966, ISSN:0035-8711, ISSN:1365-2966

In heart failure, specific target doses for each drug are recommended, but some patients receive suboptimal dosing, others are undertreated or remain chronically in a titration phase, despite having no apparent contraindication or intolerance. We assessed the association of different levels of adherence to guidelines with outcomes in patients with heart failure and reduced ejection fraction (HFrEF).Medical records of patients with HFrEF followed at our heart failure (HF) clinic for at least 6 months (n = 511) were reviewed and patients categorized as: 1) optimized (25.4%); 2) in-titration (29.0%); 3) undertreated (32.7%); and 4) intolerant/contraindicated (12.9%). Risk of mortality or HF events (hospitalization, emergency visit or ambulatory administration of intravenous diuretics) within one year was assessed using Cox regression models and Kaplan-Meier curves.Compared to optimized patients, those intolerant (HR: 4.60 [95%CI: 2.23-9.48]; p 0.0001) had the highest risk of outcomes, followed by those undertreated (3.45 [1.78-6.67]; p = 0.0002) and in-titration (1.99 [0.97-4.06]; p = 0.0588). Overall predictors of outcomes included loop diuretics' use (4.54 [2.39-8.60]), undertreatment (2.38 [1.22-4.67]), intolerance/ contraindication to triple therapy (3.08 [1.47-6.42]), peripheral vascular disease (2.13 [1.29-3.50]) and NYHA class III-IV (1.89 [1.25-2.85]); all p 0.05.Level of adherence to guidelines is associated with outcomes, with intolerant/contraindicated patients having the worst prognosis and those undertreated and in-titration at intermediate risk compared to those optimized. Up-titration of therapy should be attempted whenever possible, considering patients' limitations, to potentially improve outcomes.

Perivascular adipose tissue (PVAT) regulates vascular health. Dietary methionine restriction (MetR) impacts age-related adiposity, and this study addresses its effects in PVAT.Male C57BL/6 mice at 8, 52, and 102 weeks of age were fed a standard (0.86%) or low-methionine (0.12%) diet for 52 weeks in 8-week-old and 52-week-old mice and for 15 weeks in 102-week-old mice.Mice with dietary MetR were resistant to weight gain and maintained a healthy blood profile. Aging increased lipid accumulation, and MetR reversed this phenotype. Notch signaling in inguinal white adipose tissue (iWAT) was decreased by MetR but increased in gonadal white adipose tissue. However, the Notch phenotype of brown adipose tissue (BAT) was not affected by MetR. Uncoupling protein 1 (UCP1) was increased in PVAT, iWAT, and BAT by MetR when initiated in young mice, but this effect was lost in middle-aged mice.Lipid in mouse PVAT peaked at 1 year of age, consistent with peak body mass. MetR reduced body weight, normalized metabolic parameters, and decreased lipid in PVAT in all age cohorts. Mice fed a MetR diet from early maturity to 1 year of age displayed an increased thermogenic adipocyte phenotype in iWAT, PVAT, and BAT, all tissues with thermogenic capacity.

The BETTER (BEhaviors, Therapies, TEchnologies and hypoglycemic Risk in Type 1 diabetes) registry is a type 1 diabetes population surveillance system codeveloped with patient partners to address the burden of hypoglycemia and assess the impact of new therapies and technologies. The aim of this report was to describe the baseline characteristics of the BETTER registry cohort.A cross-sectional baseline evaluation was performed of a Canadian clinical cohort established after distribution of an online questionnaire. Participants were recruited through clinics, public foundations, advertising and social media. As of February 2021, 1,430 persons ≥14 years of age and living with type 1 diabetes or latent-autoimmune diabetes (LADA) were enrolled. The trial was registered on ClinicalTrials.gov (NCT03720197).Participants were (mean ± standard deviation) 41.2±15.7 years old with a diabetes duration of 22.0±14.7 years, 62.0% female, 92.1% Caucasian and 7.8% self-reporting as LADA, with 40.9% using a continuous subcutaneous insulin infusion (CSII) system and 78.0% using a continuous glucose monitoring (CGM) system. The most recent glycated hemoglobin ≤7% was reported by 29.7% of participants. At least 1 episode of hypoglycemia3.0 mmol/L (level 2-H) in the last month was reported by 78.4% of participants, with a median (interquartile range) of 5 (3, 10) episodes. The occurrence of severe hypoglycemia (level 3-H) in the last 12 months was reported by 13.3% of participants. Among these, the median number of episodes was 2 (1, 3).We have established the first surveillance registry for people living with type 1 diabetes in Canada relying on patient-reported outcomes and experiences. Hypoglycemia is a highly prevalent burden despite a relatively wide adoption of CSII and CGM use.

It is widely recognized that the most effective student mental health interventions, tools, and resources are those that are solidly grounded in theory, evidence, and practice. But developing interventions in this way can be a time-consuming, challenging process. This article describes the process of developing a classroom resource to build social emotional learning skills among high school students in Ontario. The resource was informed by the latest research evidence while also being sensitive to the implementation context and needs of educators and students. In creating, evaluating, and revising these resources over several years, lessons have emerged about what it takes to navigate inherent challenges, balance competing needs and priorities, and ultimately develop an intervention that is both evidence-informed and implementation sensitive. Flexible funding, effective partnerships, and a commitment to contextual responsivity are key.

Mail-delivered get-out-the-vote (GOTV) field experiments have been found to increase voter turnout in some but not all contexts. We hypothesize that mail-delivered GOTV interventions are more successful in low-salience elections and test this in a systematic way for the first time. Relying on a systematic literature review and a meta-regression framework, we find that primary elections have a strong and significant positive impact on the success of mail-delivered GOTV interventions, whereas other commonly used measures of election salience, such as voter turnout, margin of victory, and a dummy for local elections, do not. These results highlight the possibility of fostering voter turnout using GOTV mail messages, especially in primary elections.

To develop a machine learning (ML) algorithm to predict outcome of primary cytoreductive surgery (PCS) in patients with advanced ovarian cancer (AOC) METHODS: This retrospective cohort study included patients with AOC undergoing PCS between January 2017 and February 2021. Using radiologic criteria, patient factors (age, CA-125, performance status, BRCA) and surgical complexity scores, we trained a random forest model to predict the dichotomous outcome of optimal cytoreduction (1 cm) and no gross residual (RD = 0 mm) using JMP-Pro 15 (SAS). This model is available at https://ipm-ml.ccm.sickkids.ca.One hundred and fifty-one patients underwent PCS and randomly assigned to train (n = 92), validate (n = 30), or test (n = 29) the model. The median age was 58 (27-83). Patients with suboptimal cytoreduction were more likely to have an Eastern Cooperative Oncology Group 3-4 (11% vs. 0.75%, p = 0.004), lower albumin (38 vs. 41, p = 0.02), and higher CA125 (1126 vs. 388, p = 0.012) than patients with optimal cytoreduction (n = 133). There were no significant differences in age, histology, stage, or BRCA status between groups. The bootstrap random forest model had AUCs of 99.8% (training), 89.6%(validation), and 89.0% (test). The top five contributors were CA125, albumin, diaphragmatic disease, age, and ascites. For RD = 0 mm, the AUCs were 94.4%, 52%, and 84%, respectively.Our ML algorithm demonstrated high accuracy in predicting optimal cytoreduction in patients with AOC selected for PCS and may assist decision-making.

Experiences of early life adversity pose significant psychological and physical health risks to exposed individuals. Emerging evidence suggests that these health risks can be transmitted across generations; however, the mechanisms underlying the intergenerational impacts of maternal early-life trauma on child health remain unknown.The current study used a prospective longitudinal design to determine the unique and joint contributions of maternal childhood trauma (neglect and abuse) and maternal prenatal and postnatal mental health (anxiety and depressive symptoms) (N = 541) to children's resting frontoamygdala functional connectivity at 6 years (N = 89) and emotional health at 7-8 years, as indexed by parent-reported internalizing problems and child self-reported anxiety and depressive symptoms (N = 268-418).Greater maternal childhood neglect was indirectly associated with greater internalizing problems serially through a pathway of worse maternal prenatal and postnatal mental health (greater maternal anxiety and depressive symptoms). Worse maternal postnatal mental health was also uniquely associated with more negative child frontoamygdala resting-state functional connectivity, over and above maternal childhood trauma (both neglect and abuse) and prenatal mental health. More negative frontoamygdala functional connectivity was, in turn, associated with poorer child emotional health outcomes.Findings from the current study provide support for the existence of intergenerational influences of parental exposure to childhood trauma on childhood risk for psychopathology in the next generation and point to the importance of maternal factors proximal to the second generation (maternal prenatal and postnatal mental health) in determining the intergenerational impact of maternal early experiences.

Purpose To evaluate outcomes of ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) with donor corneas preserved at 31°C in Cornea Syn®, a medium formulated with recombinant human serum albumin (rHSA) to replace foetal calf serum, and deswelled-transported in the xeno-free medium Cornea Trans®. Methods Prospective, multicentre, open-label study. We evaluated the endothelial cell loss (ECL) as the percentage variation of the endothelial cell density (ECD, cells/mm2) between 6 and 12 months after surgery, corneal transparency and thickness at 12 months, and adverse events within 12 months. Endothelial lenticules of mean 89 μm, ECD ≥ 2300 cells/mm2, minimum signs of cell mortality or morphology alterations, were dissected by microkeratome in the eye bank, and grafted in patients ≥ 18 years without corneal neovascularisation, conjunctivalization, or blinking impairment. Results Thirty-five patients underwent UT-DSAEK, 3 showed primary failure, 1 late failure, and 2 skipped the 6-month visit. We analysed data from 29 patients, 27 with Fuchs endothelial corneal dystrophy (FECD) and 2 with pseudophakic bullous keratopathy (PBK). The median ECL between 6 and 12 months was 2.6% ( p = .054, CI 0 to 12.5) and the absolute mean (SD) was 158.4 (364.1) cells/mm2. After 12 months, 96.5% of corneas were clear, with mean pachymetry of 585.9 (50.4) µm. Conclusions The ECL rate after UT-DSAEK match overall that observed in DSAEK or UT-DSAEK models of endothelial survival and the overall safety compared that reported for similar follow-up. Corneas maintained in Cornea Syn® and Cornea Trans® did not affect the ECD and functional outcomes of UT-DSAEK up to 12 months.

Vitamin K antagonists (VKAs) are frequently prescribed to patients with congenital heart disease (CHD) for atrial arrhythmias or Fontan palliation, but there is a paucity of data regarding time spent in the therapeutic range (TTR). We sought to determine the TTR in patients with CHD and atrial arrhythmias or Fontan palliation prescribed VKAs and explore associations with thromboembolic and bleeding events.A multicentre North American cohort study was conducted on patients with CHD who received VKAs for sustained atrial arrhythmia or Fontan palliation. TTR was calculated using the Rosendaal linear interpolation method. Generalized estimating equations were used to explore factors associated with time outside the therapeutic range.A total of 567 patients, aged 33 ± 17 years, 56% female, received VKAs for 11.5 ± 8.4 years for atrial arrhythmias (63.0%) or Fontan palliation (58.0%). CHD was simple, moderate, and complex in 10.8%, 20.3%, and 69.0%, respectively. Site investigators perceived good control over international normalized ratio (INR) levels in most patients (75.3%), with no or minor compliance or adherence issues (85.6%). The mean TTR was 41.9% (95% confidence interval [CI], 39.0%-44.8%). Forty-seven (8.3%) and 34 (6.0%) patients had thromboembolic and bleeding events, respectively. Thromboembolic events were associated with a higher proportion of time below the therapeutic range (31.3% vs 19.1%, P = 0.003) and bleeding complications with a higher proportion of time above the therapeutic range (32.5% vs 19.5%, P = 0.006).Patients with CHD who receive VKAs spend42% of their time with INR levels in the therapeutic range, with repercussions regarding thromboembolic and bleeding complications.

In recent years, repair of the injured anterior cruciate ligament (ACL) has been subject to a renewed interest as novel arthroscopic techniques have been developed. Specifically, the bridge-enhanced ACL repair is a technique composed of a resorbable protein-based implant combined with autologous blood that is used to bridge the gap between 2 torn edges of a mid-substance ACL tear. This implant is believed to help facilitate healing of a primary suture repair and suture cinch and has since demonstrated noninferiority to ACL reconstruction with autograft at 2-year follow-up. The purpose of this Technical Note is to describe a step-by-step surgical technique of a mid-substance ACL repair using the bridge-enhanced ACL repair system in a case with a concomitant lateral meniscus radial repair.

Ground ice distribution and abundance have wide-ranging effects on periglacial environments and possible impacts on climate change scenarios. In contrast, very few studies measure ground ice in the High Arctic, especially in polar deserts and where coarse surficial material complicates coring operations. Ground ice volumes and cryostructures were determined for eight sites in a polar desert, near Resolute Bay, Nunavut, chosen for their hydrogeomorphic classification. Dry, unvegetated polar desert sites exhibited ice content close to soil porosity, with a

Anti-inflammatory Regulatory T cells (Tregs) are enriched in the joints of patients with osteoarthritis (OA) compared to healthy joints. Tregs maintain homeostasis through secretion of anti-inflammatory cytokines and cell-to-cell interactions including immune checkpoint signaling. Interleukin-6 (IL-6) is a pleiotropic cytokine secreted by inflamed synoviocytes and chondrocytes that can inhibit or alter Treg function. This study tested the hypothesis that neutralization of IL-6 would enable Treg anti-inflammatory function to resolve inflammation and catabolism elicited by IL-1β in an equine chondrocyte/synoviocyte/Treg tri-culture OA model. Synoviocyte/chondrocyte co-cultures were stimulated with IL-1β, and treated with αIL-6 neutralizing antibody. Activated Tregs secreting IL-10 were added in direct contact with synoviocytes to create a tri-culture. Neutralization of IL-6 partially restored Treg anti-inflammatory functions and, in combination, reduced IL-1β-stimulated synoviocyte MMP13 expression to control levels and restored Acan expression in chondrocytes. IL-6 neutralization alone decreased Il6 expression in chondrocytes and synoviocytes, mitigating IL-6 positive feedback loop. Although Tregs were the primary producers of anti-inflammatory IL-10 and IL-4, they also produced pro-inflammatory IL-17A, as detected by ELIA, which may have been responsible for incomplete rescue of synoviocyte/chondrocyte homeostasis following IL-1β stimulation. Treg secretion of IL-10, IL-4, and IL-17A was not altered by tri-culture conditions or presence of αIL-6, therefore, it was unlikely that Treg phenotype instability occurred. The significant effect of chondrocyte/synoviocyte donor, but not Treg donor, on gene expression and IL-6 concentration in conditioned media, indicated that personalized therapy considering the patient's OA status might be needed for successful implementation of immunotherapy in the context of OA.

Reduction of the diamagnetic Ti(III)/Ti(III) dimer [Cl2Ti(μ-NImDipp)]2 (1) (NImDipp = [1,3-bis(Dipp)imidazolin-2-iminato]-, Dipp = NC6H3-2,6-Pri2) with 4 and 6 equiv of KC8 generates the intramolecularly arene-masked, dinuclear titanium com-pounds [(μ-N-μ-η6-ImDipp)Ti]2 (2) and {[(Et2O)2K](μ-N-μ-η6:η6-ImDipp)Ti}2 (3), respectively, in modest yields. The compounds have been structurally characterized by X-ray crystallographic analysis and inspection of the bond metrics within the η6-coordinated aryl substituent of the bridging imidazolin-2-iminato ligand show perturbation of the aromatic system most consistent with two-electron reduction of the ring. As such, 2 and 3 can be assigned respectively as possessing metal centers in formal Ti(III)/Ti(III) and Ti(II)/Ti(II) oxidation states. Exploration of their redox chemistry reveal the ability to reduce several substrate equivalents. For instance, treatment of 2 with excess C8H8 (COT) forms the novel COT-bridged complex [(ImDippN)(η8-COT)Ti](μ-η2:η3-COT)[Ti(η4-COT)(NImDipp)] (4) that dissociates in THF solutions to give mononuclear (ImDippN)Ti(η8-COT)(THF) (5). Addition of COT to 3 yields heterometallic [(ImDippN)(η4-COT)Ti(μ-η4:η5-COT)K(THF)(μ-η6:η4-COT)Ti(NImDipp)(μ-η4:η4-COT)K(THF)2]n (6). Compounds 2 and 5 are the products of the 4-electron oxidation of 2, while 6 stands as the 8-electron oxidation product of 3. Reduction of organozides was also explored. Low temperature reaction of 2 with 4 equiv of AdN3 gives the terminal and bridged imido complex [(ImDippN)Ti(=NAd)](μ-NAd)2[Ti(NImDipp)(N3Ad)] (7) that undergoes intermolecular C-H activation of toluene at room temperature to afford the amido compound [(ImDippN)Ti(NHAd)](μ-NAd)2[Ti(C6H4Me)(NImDipp)] (8-tol). These complexes are the 6-electron oxidation products of the reaction of 2 with AdN3. Furthermore, treatment of 3 with 4 equiv of AdN3 produces the thermally sta-ble Ti(III)/Ti(III) terminal and bridged imido [K(18-crown-6)(THF)2]{[(ImDippN)Ti(NAd)](μ-NAd)2K[Ti(NImDipp)]} (10). Alto-gether, these reactions firmly establish 2 and 3 as unprecedented Ti(I)/Ti(I) and Ti(0)/Ti(0) synthons with the clear ca-pacity to effect multi-electron reductions ranging from 4 – 8 electrons.

The Let’s Talk in the Classroom (LTIC) Guide was designed to provide teachers with the education and support required to feel confident delivering mental health-related material in the Grade 7/8 classroom. The overall goal of this preliminary evaluation was to explore the acceptability, feasibility, and utility of the Guide using a mixed methods approach. A matched, pre/post-test evaluation of the Guide was conducted during the 2017/2018 school year among a sample of educators in Ontario, Canada (n = 42). Quantitatively and qualitatively, results demonstrated that teachers felt more confident and expressed fewer worries associated with teaching mental health-related lessons after engaging with the Guide and were suggestive of acceptability and utility, with continued challenges associated with feasibility identified.

The effect of Western diets in the gastrointestinal system is largely mediated by their ability to promote alterations in the immunity and physiology of the intestinal epithelium, and to affect the composition of the commensal microbiota. To investigate the response of the colonic epithelium to high-fat/high-cholesterol diets (HFHCDs), we evaluated the synthesis of host defense factors involved in the maintenance of the colonic homeostasis. C57BL/6 mice were fed an HFHCD for 3 weeks and their colons were evaluated for histopathology, gene expression, and microbiota composition. In addition, intestinal permeability and susceptibility to Citrobacter rodentium were also studied. HFHCD caused colonic hyperplasia, loss of goblet cells, thinning of the mucus layer, moderate changes in the composition of the intestinal microbiota, and an increase in intestinal permeability. Gene expression analyses revealed significant drops in the transcript levels of Muc1, Muc2, Agr2, Atoh1, Spdef, Ang4, Camp, Tff3, Dmbt1, Fcgbp, Saa3, and Retnlb. The goblet cell granules of HFHCD-fed mice were devoid of Relmβ and Tff3, indicating defective production of those two factors critical for intestinal epithelial defense and homeostasis. In correspondence with these defects, colonic bacteria were in close contact with, and invading the epithelium. Fecal shedding of C. rodentium showed an increased bacterial burden in HFHCD-fed animals accompanied by increased epithelial damage. Collectively, our results show that HFHCD perturbs the synthesis of colonic host defense factors, which associate with alterations in the commensal microbiota, the integrity of the intestinal barrier, and the host's susceptibility to enteric infections.

The neural orphan G protein coupled receptor GPR88 is predominant in the striatum and cortex of both rodents and humans, and considered a potential target for brain disorders. Previous studies have shown multiple behavioral phenotypes in Gpr88 knockout mice, and human genetic studies have reported association with psychosis. Here we tested the possibility that GPR88 contributes to Attention Deficit Hyperactivity Disorder (ADHD). In the mouse, we tested Gpr88 knockout mice in three behavioral paradigms, best translatable between rodents and humans, and found higher motor impulsivity and reduced attention together with the reported hyperactivity. Atomoxetine, a typical ADHD drug, reduced impulsivity in mutant mice. Conditional Gpr88 knockout mice in either D1R-type or D2R-type medium spiny neurons revealed distinct implications of the two receptor populations in waiting and stopping impulsivity. Thus, animal data demonstrate that deficient GPR88 activity causally promotes ADHD-like behaviors, and identify circuit mechanisms underlying GPR88-regulated impulsivity. In humans, we performed a family-based genetic study including 567 nuclear families with DSM-IV diagnosis of ADHD. There was a minor association for SNP rs2036212 with diagnosis, treatment response and cognition. A stronger association was found for SNP rs2809817 upon patient stratification, suggesting that the T allele is a risk factor when prenatal stress is involved. Human data therefore identify GPR88 variants associated with the disease, and highlight a potential role of life trajectories to modulate GPR88 function. Overall, animal and human data concur to suggest that GPR88 signaling should be considered a key factor for diagnostic and treatment of ADHD.